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Compounds for treatment of neurodegenerative diseases

a neurodegenerative disease and compound technology, applied in the field of compound treatments for neurodegenerative diseases, can solve the problems that current hdac inhibitors in the art such as tsa and saha may pose limitations in their utility, and achieve the effect of inhibiting deacetylation

Inactive Publication Date: 2006-01-05
FORUM PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010] Based on their structural biological activity properties, hydroxamic acid compounds, and methods of treating diseases either associated with or mediated by HDAC function are disclosed. Moreover, the compounds of the present invention avoid the potential limitations of compounds with TSA and SAHA-like structures in providing an effective therapy for such symptoms.
[0011] In another as...

Problems solved by technology

The currently known HDAC inhibitors in the art such as TSA and SAHA may pose limitations with respect to their utility.

Method used

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  • Compounds for treatment of neurodegenerative diseases
  • Compounds for treatment of neurodegenerative diseases
  • Compounds for treatment of neurodegenerative diseases

Examples

Experimental program
Comparison scheme
Effect test

example 1

7-Nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (2)

[0105] 1,2,3,4-tetrahydroiosquinoline (Aldrich T1,300-5, 100 gm) (11.6 g, 84.8 mmol) is added dropwise with care to stirred ice-cold concentrated H2SO4 (42.0 mL). Potassium nitrate (9.40 g., 93 mmol) is then added in small portions, taking care that the temperature of the reaction mixture does not rise above 5° C. After stirring overnight at room temperature the dark brown reaction mixture is added carefully to a stirred ice-cold concentrated NH4OH solution. The basic red reaction mixture is extracted with chloroform (three times), and the combined chloroform extracts is washed with brine and dried over anhydrous Na2SO4. Evaporation of the solvent gives a dark brown oil (14.6 g) which was taken up in EtOH (65 mL) and cooled in an ice bath. Treatment of this reddish solution with concentrated HCl (11 mL) yields a viscous yellow precipitate of the hydrochloride salt which is filtered and crystallized from methanol (250 mL) to yi...

example 2

7-Amino-1,2,3,4-tetrahydroisoquinoline dihydrochloride (3)

[0106] 7-Nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (2) from Example 1, is placed in a Parr shaker bottle (15.0 g, 69.9 mmol) dissolved in 95% EtOH (100 mL), and to the Parr shaker bottle is added concentrated HCl (10 mL), water (25 mL), and PtO2 (0.5 g). The mixture is hydrogenated at 50 psi until no further drop in pressure was observed (about 4 hours). The yellowish suspension is filtered through Celite and evaporated to dryness to afford a yellowish solid which is made basic with 10% NaOH solution (adequate care is exercised in catalyst disposal). Extraction of the basic solution with CHCl3 (three times), followed by drying over anhydrous Na2SO4 and evaporation of the solvent, yields a reddish yellow solid (9.54 g, 92.2%): mp=110-112. 7-Amino-1,2,3,4-tetrahydroisoquinoline dihydrochloride (3) is recrystallized from aqueous MeOH as buff colored needles, mp=290° C.

example 3

7-Cyano-1,2,3,4-tetrahydroisoquinoline Hydrochloride (4)

[0107] 7-Amino-1,2,3,4-tetrahydroisoquinoline dihydrochloride (3) from Example 2 (0.75 g, 5.1 mmol) is dissolved in concentrated HCl (1.75 mL) and water (2 mL) and stirred in an ice bath, giving a red solution. To this solution is added dropwise NaNO2 (0.35 g, 5.1 mmol) dissolved in water (2 mL). After 15 minutes stirring, a positive starch-iodide test is obtained and the excess HNO2 is destroyed by the addition of urea (0.10 g).

[0108] In a second flask, a solution of NaOH (0.50 g in 1.5 mL water) and KCN (1.63 g in 5 mL of water) is prepared, and benzene (5 mL) is added. The suspension is chilled in an ice bath, and to it is added a solution of Ni2SO4.6H2O (1.3 g, 5 mmol) in 2.5 mL water). The color of the resulting mixture changes to yellow-brown. To this mixture is added dropwise with vigorous stirring the diazotized solution. Brisk evolution of N2 is observed, and the reaction mixture is allowed to warm to room temperatur...

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Abstract

The present invention relates to a class of small molecule hydroxamic acid compounds capable of inhibiting histone deacetylases (HDACs). The present invention also relates to methods of preparation of hydroxamic acid HDAC inhibitor compounds of the invention, which are N-substituted-1,2,3,4-tetrahydroisoquinoline hydroxamic acid derivatives, and their incorporation into pharmaceutical compositions and methods of administration. The present invention also relates to N-substituted-1,2,3,4-tetrahydroisoquinoline hydroxamic acid derivatives, which may be prepared as a hydroxamic acid HDAC inhibitor compound library that can be utilized in screening methods known in the art.

Description

RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application Ser. No. 60 / 567,673, filed on May 3, 2004, the contents of which are incorporated herein by reference.BACKGROUND OF THE INVENTION [0002] Histone deacetylases (HDACs) are important zinc hydrolases that are responsible for the regulation of gene expression through deacetylation of the N-acetyl lysine residues of histone proteins and other transcriptional regulators. HDACs are involved in cell-cycle progression and differentiation. HDAC inhibitors, such as trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA), have anti-tumor effects and can inhibit cell growth, induce terminal termination, and prevent the formation of tumors in mice models. [0003] Evidence from recent studies suggest that transcriptional dysregulation may contribute to the molecular pathogenesis of Huntington's disease (HD). HD is an inherited, progressive neurological disorder that is caused by a CAG / polyglutamine r...

Claims

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Application Information

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IPC IPC(8): A61K31/4709C07D43/02C07D41/02A61K31/00A61K31/47C07D213/00C07D217/06C07D217/08C07D401/06C07D401/10C07D409/12C07D417/12C07D471/04
CPCA61K31/47C07D217/02C07D217/06C07D217/08C07D471/04C07D401/10C07D401/12C07D409/12C07D417/12C07D401/06
Inventor CUMMINGS, CHRISTOPHER J.LOWE, DAVID A.RIPKA, WILLIAM C.
Owner FORUM PHARMA
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